Development of a novel class of immunotherapeutic antibody for metastatic prostate cancer

开发一类新型治疗转移性前列腺癌的免疫治疗抗体

• 批准号: 9919279
• 负责人: GRANT H RISDON
• 金额: $ 81.89万
• 依托单位: CANCURE, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919279
• 关键词: Address; Androgen Receptor; Antibodies; Antigen-Antibody Complex; Antigens; Benchmarking; Biochemical; Biophysics; CD3 Antigens; CD34 gene; CD8-Positive T-Lymphocytes; Cancer Center; Cancer Patient; Cell surface; Clinical; Clinical Trials; Collaborations; Colon; Consult; Data; Development; Development Plans; Fostering; Future; Goals; Human; Immune; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Impairment; Licensing; Ligands; Mediating; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Monoclonal Antibodies; Myeloid-derived suppressor cells; Natural Killer Cells; Neoplasm Metastasis; Outcome; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Pre-Clinical Model; Production; Prostate; Recommendation; Risk; Safety; Serum; Signaling Molecule; Solid Neoplasm; Stress; Surface; Technology; Testing; Toxic effect; Toxicology; Translating; Treatment Efficacy; base; checkpoint therapy; clinical development; clinical toxicology; commercialization; drug development; first-in-human; human monoclonal antibodies; immune checkpoint blockade; improved; interest; macrophage; meetings; mouse model; mutant; nonhuman primate; novel; novel therapeutics; pre-clinical; preclinical development; preclinical study; preclinical toxicity; prostate cancer cell; receptor; safety testing; self-renewal; targeted treatment; tumor

Abstract The overarching goal of this application is to development a novel immunotherapy for treatment of metastatic prostate cancer (mPC), a lethal with limited treatment options. Immunotherapy has significantly improved survival in patients with a variety of solid tumors, however it has only presented limited efficacy in metastatic prostate cancer patients. Thus, there is an unmet need to develop effective immunotherapies for mPC. Based on the findings that metastatic prostate tumor cells convert the stress-induced immune stimulatory cell surface molecule, the MHC I Chain related molecule (MIC), to a highly immune suppressive soluble MIC (sMIC). CanCure has developed a first-in-class sMIC-targeting monoclonal antibody (mAb) B10G5 that has demonstrated remarkable efficacy in eliminating prostate metastatic as a single agent in preclinical models. When used in combination, B10G5 synergizes with immune checkpoint blockade therapy and eliminates immune checkpoint therapy-induced colon toxicity. We show that B10G5 confers its therapeutic efficacy through two defined mechanisms of action. CanCure has formulated the B10G5 mAb for human use (designated and huB10G5) and tested the safety of huB10G5 in pilot toxicity study in non-human primates (NHP). HuB10G5 is ready for IND-enabling studies. To achieve our goal, CanCure proposes two specific Aims: 1) Determine therapeutic efficacy of B10G5 with frontline AR-targeting therapy for mPC; 2) Conduct pre-clinical IND-enabling GLP production and toxicology study. The outcome of proposed study would define the path and provide a strong scientific rationale on how to translate our new therapy into early clinical trials. .

摘要 本申请的总体目标是开发一种用于治疗转移性乳腺癌的新型免疫疗法。 前列腺癌（mPC），一种治疗选择有限的致命疾病。免疫治疗显著提高了生存率 然而，在患有各种实体瘤的患者中，它仅在转移性前列腺中表现出有限的功效。 癌症患者。因此，存在开发用于mPC的有效免疫疗法的未满足的需求。基于 转移性前列腺肿瘤细胞转化应激诱导的免疫刺激细胞表面 MHCI链相关分子（MIC），与高度免疫抑制性可溶性MIC（sMIC）。 CanCure开发了一流的sMIC靶向单克隆抗体（mAb）B10 G5， 在临床前模型中作为单一药剂显示出消除前列腺转移的显著功效。 当联合使用时，B10 G5与免疫检查点阻断疗法协同作用，并消除免疫反应。 检查点疗法诱导的结肠毒性。我们表明，B10 G5通过两个途径赋予其治疗功效， 明确的行动机制。CanCure已经配制了B10 G5 mAb用于人用（指定和 huB 10 G5），并在非人灵长类动物（NHP）中的初步毒性研究中测试了huB 10 G5的安全性。HuB 10 G5是 准备进行IND赋能研究。为了实现我们的目标，CanCure提出了两个具体目标：1）确定 B10 G5与一线AR靶向治疗对mPC的疗效; 2）进行临床前IND启用 GLP生产和毒理学研究。拟议研究的结果将确定道路，并提供一个强有力的 如何将我们的新疗法转化为早期临床试验的科学原理。 .